Genetics
A single-nucleotide KMT2D mutation has outsize impact
Researchers found that a tiny genetic change in KMT2D can replicate the core Kabuki Symptoms seen when the whole gene fails - with one key exception.
A single, subtle change to the KMT2D gene is enough to produce many of the core symptoms of Kabuki syndrome in mice. This finding comes from a new mouse model engineered to carry a specific genetic variant taken from a person with Kabuki. The research suggests that even when the KMT2D protein is stable and its main enzyme function appears intact, significant developmental problems can still occur.
For over a decade, most research into potential Kabuki therapies has relied on a mouse model where the Kmt2d gene is essentially broken, mimicking a total loss of function. This model shows key features like growth deficiency, a distinct facial profile, low IgA antibody levels, and visuospatial memory problems. However, about 15-30% of people with Kabuki syndrome have a different type of mutation called a missense variant, where a single "letter" in the gene's code is swapped for another.
To understand how these missense variants cause disease, scientists used CRISPR gene-editing to create mice with a specific human variant, known as R5230H. This change alters a single amino acid—an arginine to a histidine—in a crucial region of the KMT2D protein called the FYRN domain. Computer modeling predicted the change wouldn't crumple the protein's structure but would slightly alter its electrical charge.
Surprisingly, these mice developed nearly all the physical hallmarks seen in the older, loss-of-function model. They had significant growth deficiency, craniofacial anomalies, low IgA levels, and fewer immune structures in the gut called Peyer's patches. This confirms these core symptoms are directly linked to KMT2D dysfunction and not an artifact of the older model's engineering.
However, one major difference stood out. The new R5230H mice did not develop the neurological deficits seen in the prior model. They performed normally on tests of visuospatial memory and showed no signs of anxiety-like behavior. At a cellular level, their brain structure, rates of new neuron growth (neurogenesis), and global levels of key histone methylation marks were all normal.
The new model also revealed a previously unseen problem: a high rate of kidney agenesis, where one kidney fails to develop. This occurred in about 43% of the mutant mice and provides a new way to study a common clinical issue in Kabuki syndrome. The model also showed greater severity around birth, with fewer heterozygous pups surviving the perinatal period than in the older model.
The study indicates that the R5230H variant likely disrupts KMT2D through a mechanism separate from destroying its enzyme activity. Instead, it may interfere with how the protein interacts with partner molecules, potentially affecting its recruitment to specific sites in the genome. This suggests that for some symptoms, like the neurological defects, the loss of KMT2D's catalytic "writing" function may be critical. For other core physical traits, simply perturbing the protein's other roles may be enough.
Other findings from the study:
* The patient who provided the R5230H variant had a higher-than-expected IQ (77) and only mild intellectual disability, aligning with the milder neurological impact in the mice.
* A previous Kabuki mouse model with a different missense variant acted more like a partial loss-of-function and only showed symptoms when both gene copies were mutated, unlike the human condition.
* The authors note that using only female mice in behavioral tests or the possibility that mouse models may only capture moderate-to-severe intellectual disability could also explain the lack of neurological deficits.
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